One of the most profound and disturbing aspects associated with Alzheimer's disease (AD) is the loss of cognitive abilities. Concomitant with this cognitive decline are well-documented biochemical and structural changes which occur in neuronal tissue and result in an accumulation of neurofibrillary tangles (NFT) and senile plaques characteristic of AD. Senile plaques are composed of fragments of the amyloid precursor protein, whereas NFT are composed primarily of paired-helical filaments (PHF). The latter are in turn composed principally of the microtubule-associated tau protein. Although, the genesis of PHF is not known, there is considerable evidences suggesting that PHF-tau proteins are "abnormally" phosphorylated. Thus, it has been proposed that PHF formation may result from the lack of proper regulation of protein kinases or phosphatases. In order to identify kinases that may phosphorylate PHF-tau in AD, the applicants have isolated and characterized PHF-associated kinases. By immunoblotting and immunoelectron microscopy they have identified alpha-calcium-calmodulin-dependent protein kinase II (a-CaM kinase) immunoreactivity associated with a globulus (membranous-like) structure found at the ends of isolated PHF. Since a-CaM kinase is involved in a number of physiological processes including memory, its association with PHF could be important in PHF genesis or in the etiology of AD. In order to further understand what role a-CaM kinase plays in AD, the applicants propose to determine if a-CaM kinase is indeed localized to PHF in AD brain by immunoelectron microscopy. They also propose experiments to further characterize the globulus structure found at the ends of PHF to which a-CaM kinase is localized to determine if it is indeed membranous. In addition, they propose to determine what effects overexpression of brain specific CaM kinases have on tau functions in vivo. Finally, their long term goals are to determine how these and any other PHF-associated kinases lead to the formation of PHF in AD. These studies will provide valuable information on the role of brain CaM kinases on tau function in both normal development and AD.